The Mitotic Cycle

Growth as a result of division is based on mitotic cell divisions. The events of mitosis will be taken for granted here. In the stages of 

In every reputable textbook it is stated that, in contrast to meiosis, mitotic division entails exact chromosome duplication. Thus, each daughter cell carries the same genetic information as the parent cell. Since we already know that DNA is the genetic material of higher organisms, we must direct our attention to the DNA when considering evidence for this statement. 

If each daughter cell is to contain a complement of DNA identical with that of the parent cell, then the DNA of the parent cell must be reduplicated identically before mitosis. For the moment let us ignore the word identical and first ask only whether a DNA reduplication of this kind can be apprehended quantitatively. This is indeed so. In the meristem zones of plants, cells pass through a mitotic cycle or cycle of DNA synthesis from one mitosis to the next (Fig. 134). Directly after a division there is a postmitotic phase without DNA synthesis. This is followed by a phase of DNA in which the DNA has been shown by quantitative measurements to double. After that there is another phase without DNA synthesis which precedes the next mitosis and which is thus called premitotic. It leads to mitosis and subsequent division. The daughter cells which arise can pass through the same cycle again, provided they have retained their ability to divide. 

---

Rieder CL, Palazzo RE 1992 Colcemid and the mitotic cycle. J Cell Sci 102 387-392 Saez C, Japon MA, Ramos-Morales F et al 1999 hpttg is over-expressed in pituitary adenomas and other primary epithelial neoplasias. Oncogene 18 5473—5476... 

Qin, X., and Samow, P. (2004). Preferential translation of internal ribosome entry site-containing mRNAs during the mitotic cycle in mammalian cells. J. Biol. Chem. 279, 13721-13728. 

Aminouracil produces a block in the mitotic cycle of various plants. For example, cessation of mitosis occurred in Vida faba roots incubated 24 h with this compound [392—394]. Depending on different experimental conditions, thymidine or thymidylic acid may or may not alleviate these effects [392—394]. It was concluded that 5-aminouracil depressed the rate of DNA synthesis, which led to an accumulation of cells in the S phase. After removal of the agent, DNA synthesis resumed. Similar results have been observed with Allium cepa and Haplopappus gracilis [395, 396]. Inhibition of guanosine incorporation into RNA of meristematic cells in Vida faba by 5-aminouracil was also reported [397]. 

Azathioprine is a phase-specific drug that is toxic to cells during nucleic acid synthesis. Phase-specific drugs are toxic during a specific phase of the mitotic cycle, usually the S-phase, when DNA synthesis is occurring, as opposed to cycle-specific drugs that kill both cycling and intermitotic cells. 

Fast neutrons were the first nonconventional radiation used in cancer therapy. Fast neutrons (a high-LET radiation) were introduced for the following radiobiological reasons (1) a reduction of the OER with increasing LET (2) a reduction in the difference in radiosensitivity related to the position of the cells in the mitotic cycle (3) and less repair and thus less clinical relevance of the different repair mechanisms. The best and clinically proven indications for fast neutrons are salivary gland tumors, locally advanced prostatic adenocarcinomas, and slowly growing, well-differentiated sarcomas. 

A reduction of the differences in radiosensitivity related to the position of the cell in the mitotic cycle... 

Fig. 8 illustrates how increasing LET reduces the differences in radiosensitivity related to the position of the cells in the mitotic cycle [31]. Cells in stationary phase and in S phase are significantly more radio-resistant than mitotic cells. 

Figure 8 Differences in radiosensitivity with the position of the cells in the mitotic cycle. The differences are reduced with increasing LET. Single-hit inactivation coefficients (a) for homogeneous populations of mitotic, G1 -phase, and stationary phase Chinese hamster cells irradiated with 220-kV x-rays and various charged particle beams, as a function of median LET (in keV pm ). (From Ref. 31.)...

Suurmeijer, A. J. H., and Boon, M. E. 1999. Pretreatment in a high-pressure microwave processor for MIB-1 immunostaining of cytological smears and paraffin tissue sections to visualize the various phases of the mitotic cycle./. Histochem. Cytochem. 47 1015-1020. 

Liver regeneration takes place in three phases (7.) pre-replicative phase, with preparation for mitosis, (2.) proliferative phase, with wave-like mitoses at 6—8 hour intervals, and (3.) restitution phase, with reconstitution of the hver structure. There are two stages to this whole process (7.) priming, which is the transition of latent hepatocytes (Go) into the mitotic cycle (Gp — this reversible process is triggered by cytokines, hormones or other permissive substances, whereby the cells proliferate due to stimulation by the growth factor (2.) progression is the transition from Gi to DNA synthesis (S) — this transition point from Gi to S is marked by the expression of cyclin Di. 

Finally, cytokinins were reported to activate the p34 protein kinase in tobacco pith cells [93]. Cells not supplied with cytokinin (benzylaminopurine) became arrested in Gj phase of the mitotic cycle and contained inactive kinase. The kinase activation process, which appears to involve the phosphorylation of tyrosine at sites within the kinase molecule, could be relevant for the remodelling of the cytoskeleton prior to mitosis. Activated p34 protein kinase was shown specifically to bind to and also to disintegrate MTs of pre-prophase bands [94,95]. Also relevant in this respect is the finding that plant cyclins associate with various MT arrays during the mitotic cycle, including the preprophase band [96]. These reports indicate that advances in understanding of the controls of MT activity by cytokinins are at last in prospect. 

DiCicco-Bloom, E. and Black, I.B. (1988) Insulin growth factors regulate the mitotic cycle in cultured rat sympathetic neuroblasts. Proc. Natl. Acad. Sci. USA 85 4066-4070. 

S Additional information <228> (<228>, may function in a checkpoint control which couples DNA replication to mitosis. The level of the RPKl transcript is extremely low and constant throughout the mitotic cycle. However it is regulated during cellular differentiation, being decreased in a-factor-treated cells and increased late in meiosis in a diploids. Rpkl is involved in a pathway that coordinates cell proliferation and differentiation [417]) [417]... 

The model not only provides a plausible explanation for the origin of the threshold levels observed in the action of cyclin and cdc2 kinase during the mitotic cycle, but it also shows how these thresholds are necessarily linked to the time delays that play a primary role in the onset of oscillations (Murray Kirschner, 1989a F61ix et al, 1990). 

The above discussion explains why the period of the oscillations is largely determined by the rate of accumulation of cyclin up to the threshold beyond which it activates cdc2 kinase. This phase of accumulation, which corresponds to the interphase of the mitotic cycle in amphibian embryonic cells, is indeed longer than the mitotic phase, which corresponds to the peak in cdc2 kinase activity. Such a result holds with the observation (Murray Kirschner, 1989b) that an increase in the rate of cyclin accumulation shortens the period of the cell cycle. 

The second view did not rely on the existence of an oscillator independent from mitosis and stated that the latter is an integral part of the mechanism underlying the cell division rhythm (Tyson Sachsenmaier, 1978, 1984). The rhythm would thus have a simpler origin, due to the discontinuity of cell division. Tyson Sachsenmaier (1978) compared such a rhythm to the effect of a thin stream of sand constantly falling on a pan on one side of a balance when a critical weight is reached, the pan tips over and, once emptied, recovers its equilibrium position. The sand then accumulates again until the next flip. In this phenomenon, the phase of abrupt decrease that precedes the replenishment phase consists of the discontinuous reversal of the position of the pan. This image could apply to the case of the mitotic cycle the latter could result from the accumulation of a mitotic factor up to a threshold beyond which the discontinuity of cell division would occur. No oscillation should take place in the absence of mitosis. 

Experiments carried out on mitosis in Physarum polycephalum (Kaufmann Wille, 1975 Tyson Sachsenmaier, 1978) did not allow a definitive conclusion in favour of one of the two views. The difficulty came from the fact that, short of the identification of the true biochemical variables driving the cell cycle, it was difficult to demonstrate the existence of a limit cycle in Physarum. Experiments based on the fusion of two plasmodia taken at different phases of the mitotic cycle or on the effect of heat shocks aimed at demonstrating the existence of a singular point from which the limit cycle would be reached with an indefinite phase (Winfree, 1974,1980,1987). These experiments did not allow the distinction to be made between a limit cycle characterized by relaxation oscillations and a discontinuous mechanism of the type discussed above. 

Zeligs. J. D., and Wollman, S. H. (1979). Mitosis in rat thyroid epithelial cells in vivo I. Ultrastructural changes in cytoplasmic organelles during the mitotic cycle. J. Ultrastruct. Res. 66,53-77. 

The duration of the mitotic cycle in Vida varies between 18 and 22 hr at 19°C. In an autoradiographic study with tritiated thymidine as radioactive DNA precursor, Evans and Scott (1964) found the mean duration of the mitotic cycle in main roots to be 19.3 hr. Of this time, 17.3 hr were spent in interphase. 

With the aid of the binucleate cell technique (Kihlman, 1955a Gimenez-Martin et al. 1965), we have determined the mean duration of the mitotic cycle in A. proliferum to be 18-20 hr at 19°C. In autoradiographic experiments, a mean duration of 5 hr was found for the Gg period of interphase (Kihlman, unpublished). The satellite proved to be late replicating. 

The period of treatment should be kept as short as possible. The longer the duration of the mitotic cycle, the longer the period of treatment can be. One to two hours is a suitable treatment time when the mitotic cycle is 18-24 hr, as it is in Vida and Allium, Short periods of treatment make it considerably easier to determine the stage(s) of the mitotic cycle which is sensitive to the chromosome-breaking effect of the chemical. However, a suspected mutagen cannot be declared without action just because it does... 

It should be emphasized that the time between the beginning of the treatment and the appearance of the aberrations in anaphase (or metaphase) can be used as an indicator of the stage affected only when the mitotic activity is not markedly suppressed by the treatment. The longer the period between treatment and fixation, the less accurate is the time method. An accurate determination of stage sensitivity in root tips can be obtained only by using cells labeled at a particular stage of the mitotic cycle (for methods of labeling, see Kihlman, 1966). 

Hughes, A. (1952). The Mitotic Cycle. Academic Press, New York. 

Guttes, E. W., P. C. Hanawalt, and S. Guttes. 1967. Mitochondrial DNA synthesis and the mitotic cycle iaPhysarum polycephalum. Biochim. Biophys. Acta, 142 181-194. 

Sisken, J. E. 1964. Methods for measuring the length of the mitotic cycle and the timing of DNA synthesis for mammalian cells in culture. In Methods in Cell Physiology, Prescott, D. M., ed.. New York, Academic Press, Inc, pp. 387-400. 

Woodard, J. C., E. Rasch, and H. Swift. 1961. Nucleic acid and protein metabolism during the mitotic cycle in Viciafabia, J. Biophys. Biochem. Cytol., 9 445-462. 

---